PROJECT SUMMARY/ABSTRACT The Breast Cancer Program (BrCP) consists of 72 members (60 primary, 12 associate) from 25 departments. The program is led by Dr. Kelly K. Hunt, breast surgical oncologist and clinical investigator; Dr. Khandan Keyomarsi, laboratory-based investigator; and Dr. Debu Tripathy, breast medical oncologist and clinical investigator. The major scientific goal of the BrCP is to elucidate mechanisms of cancer evolution and metastasis that can be translated into new treatment strategies for breast cancer patients. There are 3 themes: 1) Genetic Alterations and Breast Cancer Evolution, 2) Biology of Established Breast Cancer, and 3) Targeted Therapy in Breast Cancer. They have led to 3 specific aims: Aim 1: to elucidate the molecular and genomic evolutionary basis of breast cancer development and progression; Aim 2: to examine the deregulation of signal transduction, DNA repair, cell-cycle, and differentiation pathways in breast cancer that could provide therapeutic targets; Aim 3: to leverage scientific discoveries into novel therapeutics and bioassays for breast cancer management and conduct innovative clinical trials and population-based studies that can reduce the burden of disease in the Texas population. The annual direct peer-reviewed funding totals $5.4M, of which $3.2M (60%) is from NCI grants. Since the last competitive renewal, the program has authored 1,092 published papers: 562 (51%) represent intra-programmatic collaborations, 360 (33%) represent inter-programmatic collaborations, and 695 (64%) represent external collaborations. Forty-six percent of articles have appeared in journals with IF >5 and 18% have appeared in journals with IF >10, including Cancer Discov, Cell, JAMA, J Clin Oncol, Lancet Oncol, Nature, Nat Genet, and the N Engl J Med. Program members use all 14 shared resources. During the last grant period, research substantially influenced the clinical practice for treatment of bone metastasis from breast cancer. Another development was the Neo-Bioscore staging system, which improves upon the previously validated CPS+EG system and allows its application in patients with ERBB2-positive disease. The CPS+EG system influenced the incorporation of biological factors into the eighth edition of the American Joint Committee on Cancer breast cancer staging system. Program members have also made several impactful discoveries that improve our understanding of the mechanisms leading to subtypes of breast cancer, especially those with limited therapeutic options. Studies carried out via inter-programmatic collaborations on triple-negative breast cancers demonstrate a common evolutionary lineage along with a minor subpopulation of nonclonal cells, suggesting that the majority of copy-number aberrations are acquired at the earliest stages of tumor evolution (Gao R et al, Nat Genet, 2016); unveiling a molecular link among epithelial-mesenchymal transition, therapy resistance, and metastasis (Zhang J et al, Nat Cell Biol, 2013); and identifying iDAPK1 as a novel therapeutic strategy in triple- negative breast cancers with p53 mutations by modulating the mTOR/S6 pathway (Zhao J et al, J Clin Invest, 2015).